This project aims to define the physiologic and mechanistic functions of RGS proteins, which regulate signaling by hundreds of G protein coupled receptors in the cardiovascular, immune, nervous and sensory systems. Currently it focuses on RGS2, which the P.I. has discovered is an important regulator of blood pressure. The central hypothesis is that RGS2 regulates blood pressure in part by controlling signaling pathways governing vascular tone. This hypothesis is supported by preliminary data showing that: 1) RGS2 knockout mice are hypertensive;2) arteries from RGS2 knockout mice display augmented contraction and unpaired relaxation;3) vascular smooth muscle cells from RGS2 knockout mice exhibit augmented vasoconstrictor-induced Ca2+ signaling and impaired vasodilatory signaling by cGMP-dependent protein kinase (PKG). This project will determine the molecular mechanisms by which RGS2 in concert with PKG regulates signaling pathways that control vascular contraction and relaxation in vascular smooth muscle cells from resistance arteries. In so doing, this project will reveal new mechanistic principles of blood pressure regulation that may be impaired in human hypertension, which would contribute to development of mechanism-based diagnosis and treatment of this poorly understood disease.